Role of nitric oxide in neurodegenerative diseases

Besides its role as a mediator of several physiological functions, nitric oxide appears to be a neurotoxin under conditions of excessive production, which suggests a role for nitric oxide in neurodegenerative diseases. An increasing body of evidence has implicated excitotoxicity as a mechanism of cell death in both acute and chronic neurologic diseases. Activation of excitatory amino acid receptors leads to activation of neuronal nitric oxide synthase by an increase in intracellular calcium concentrations. Nitric oxide may inhibit key enzymes of energy metabolism, damage DNA, deplete intracellular glutathione, and react with superoxide to form peroxynitrite. The latter is a highly reactive molecule, a potent oxidizing agent known to initiate lipid peroxidation, hydroxylation and nitration of aromatic amino acid residues, and sulfhydryl oxidation of proteins, and to decompose to nitrogen dioxide and species with hydroxyl-like reactivity. There now is evidence that the neuronal production of nitric oxide and the formation of peroxynitrite occurs in vivo.